Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_000162.5(GCK):c.646G>A (p.Glu216Lys)

CA4239565

447412 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 8b2ccd2e-b05d-4b47-b1d2-c3337ab05d6f

HGVS expressions

NM_000162.5:c.646G>A

NM_000162.5(GCK):c.646G>A (p.Glu216Lys)

NC_000007.14:g.44149793C>T

CM000669.2:g.44149793C>T

NC_000007.13:g.44189392C>T

CM000669.1:g.44189392C>T

NC_000007.12:g.44155917C>T

NG_008847.1:g.44631G>A

NG_008847.2:g.53378G>A

ENST00000395796.8:c.*644G>A

ENST00000616242.5:c.646G>A

ENST00000682635.1:n.1132G>A

ENST00000345378.7:c.649G>A

ENST00000403799.8:c.646G>A

ENST00000671824.1:c.646G>A

ENST00000673284.1:c.646G>A

ENST00000345378.6:c.649G>A

ENST00000395796.7:c.643G>A

ENST00000403799.7:c.646G>A

ENST00000437084.1:c.595G>A

ENST00000616242.4:n.643G>A

NM_000162.3:c.646G>A

NM_033507.1:c.649G>A

NM_033508.1:c.643G>A

NM_000162.4:c.646G>A

NM_001354800.1:c.646G>A

NM_033507.2:c.649G>A

NM_033508.2:c.643G>A

NM_033507.3:c.649G>A

NM_033508.3:c.643G>A

Uncertain Significance

PP3 PP2

PM2 BS1

Evidence Links 0

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specification: ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GCK Version 1.2.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.646G>A variant in the glucokinase gene, GCK, causes an amino acid change of glutamic acid to lysine at codon 216 (p.Glu216Lys) of NM_000162.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.711, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Additionally, GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). The Popmax filtering allele frequency of the c.646G>A variant in gnomAD v2.1.1 is 0.00001897 (East Asian), which falls between ClinGen MDEP-established cutoffs for PM2_Supporting (0.000003) and BS1 (0.00004); thus, neither criterion will be applied. In summary, c.646G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PP3, PP2.

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.711, which is greater than the MDEP VCEP threshold of 0.70 (PP3).

PP2

GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2).

PM2

The Popmax filtering allele frequency of the c.646G>A variant in gnomAD v2.1.1 is 0.00001897 (East Asian), which falls between ClinGen MDEP-established cutoffs for PM2_Supporting (0.000003) and BS1 (0.00004); thus, neither criterion will be applied.

BS1

Approved on: 2023-07-30

Published on: 2023-07-30

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